The present disclosure relates to magnetic nanoparticles and related devices and methods. More specifically, the present disclosure relates to compositions and methods of making magnetic nanoparticles having a narrow size distribution for use in diagnostics and therapeutics.
Magnetic nanoparticles (also referred to as MNPs) are attractive agents for biomedicine due to strong intrinsic magnetism that, through interaction with a magnetic field, enables their detection or influence from deep within a living subject. Rightly, magnetic nanoparticles have been studied extensively as potential contrast agents or nanoparticle materials in molecular imaging applications based on magnetic resonance imaging (MRI), as well as carriers for magnetically assisted drug delivery and hyperthermia. Recently, a new imaging modality called magnetic particle imaging (MPI) was introduced as a technique for visualizing magnetic nanoparticles in humans and animals. MPI is fast, quantitative, sensitive, and features good spatial resolution, a combination that is difficult to realize in MR imaging of magnetic nanoparticles, because MPI directly probes the large magnetic nanoparticle moment rather than its indirect effect on proton relaxation, as does MR imaging. Noteworthy recent MPI studies include in vivo, real-time imaging of magnetic nanoparticles passing through a beating mouse heart and compact, single-sided scanners that can image a patient without first inserting them into a costly and potentially claustrophobic magnetic device.
Despite much exciting progress in MPI scanner design and related image processing, relatively little effort has been spent developing magnetic nanoparticles that optimize imaging sensitivity. In fact, for MPI to successfully move beyond proof-of-principle experiments into the clinic or preclinical research laboratory, it will be important to engineer magnetic nanoparticles that are optimized for MPI. Most recent studies have used commercially available magnetic nanoparticle agents, including Resovist® (Bayer Schering Pharma, Berlin) and Feridex I.V.® (AMAG Pharmaceuticals, Lexington, Mass.; trade name Endorem™ in Europe); these are far from being magnetically optimized for MPI and thus inhibit MPI from reaching its full potential in terms of both spatial resolution and mass sensitivity. For example, in Resovist®, which to date has been the most popular material for MPI studies, it has been shown that only 3% of the total sample mass contributes noticeably to the MPI signal. More efficient nanoparticles are desired for molecular imaging applications that depend on active targeting, where for the highest sensitivity, each unit of nanoparticle is desired to generate the maximum achievable MPI signal voltage. Furthermore, for quantitative imaging, the signal intensity, and therefore magnetic nanoparticle properties, are desired to be uniform and reproducible.
In addition, magnetic nanoparticles are an attractive option for site-specific cancer therapies because they can be remotely targeted by the application of external magnetic field gradients or other active and passive targeting methods. Once localized, Magnetic Fluid Hyperthermia (MFH), a therapeutic modality that utilizes alternating magnetic fields (AMF) to dissipate heat from the resulting relaxation losses in magnetic nanoparticles, can be used to induce localized heating. Heating cancer cells (typically to ˜42-43° C.) is known to disrupt cellular metabolism making adjuvant therapy by conventional established methods more efficient. A wide range of ferromagnetic nanoparticles can be synthesized for MFH. Due to their modest magnetic characteristics, however, magnetic nanoparticles need to be optimized in terms of their morphological (size, size distribution, shape), crystallographic (phase purity) and magnetic (relaxation) characteristics for effective application in MFH.
Superparamagnetic iron oxide nanoparticles (SPIONs) composed of magnetite (Fe3O4), maghemite (Fe2O3) or a mixture of magnetite and maghemite, have been used in the clinic to enhance the T2/T2*(negative) MRI contrast [Feridex I.V.® and Combidex®—produced by AMAG pharmaceuticals, Resovist®, produced by Bayer Schering Corporation], and more recently for the treatment of iron deficiency anemia in chronic kidney disease (CKD) patients [Feraheme®—produced by AMAG pharmaceuticals]. Experimentally, SPIONs of various compositions have been used for biomedical applications such as cell labeling and separation, drug delivery, magnetic gene transfection (magnetofection), tissue repair and hyperthermia [Gupta et al, Biomaterials 2005; 26:3995-4021, Krishnan, IEEE Trans. Mag. 46, 2523-2558 (2010)].
The unique nonlinear magnetic response of SPIONs can be exploited in alternating magnetic fields to induce a detectable signal that is proportional to the ac-susceptibility (m′(H)). Applications such as MPI [Gleich and Weizenecker, Nature 2005; 435:1214-7], magnetic sentinel lymph node biopsy (SLNB) [M. Douek et al, Ann. Surg. Oncol., 21, 1237 (2013)] and MFH [R. K. Gilchrist et al, Ann. Surgery 146, 596 (1957); U. Gneveckow et al, Med. Phys. 31, 1444 (2004)], employ alternating magnetic fields in the radiofrequency range (1 1,000 kHz) applied to SPIONs. Maximum signal, especially in MPI, is generated when SPIONs with core sizes near the superparamagnetic-to-ferrimagnetic transition and uniform size distribution are used.
With clinical end-use in perspective, the first generation of SPIONs designed for either in vivo MPI or MFH therapy must be biocompatible and demonstrate appropriate circulation times to enable vascular imaging or site-specific heating, respectively. For performing first-pass and subsequent blood pool imaging, a circulation time of approximately 1 hour should provide clinicians sufficient time; for instance, Ablavar® (Lantheus Medical Imaging)—a gadolinium-based MRI blood pool agent remains in circulation for up to 1 hour [www.ablavar.com]. However, given the real-time imaging capability of MPI, even shorter circulation times may be sufficient. Ultimately, practical considerations such as the preferred administration route (intravenous injection or cardiac catheterization; the latter is preferred if in situ interventional procedures are deemed necessary) and the actual time it takes to ready patients for MPI scans will determine the optimum circulation time of SPIONs. On the other hand, studies indicate that cancer targeting—measured by targeting efficiency and not imaging speed—requires several hours (>1 hour) of circulation time [Fang et al, Eur J Pharm Sci 2006; 27:27-36, Cole et al, Biomaterials 2011; 32:2183-93]; typically, longer the circulation time, greater the probability of reaching the disease site [Albanese et al, Annu Rev Biomed Eng 2012; 14:1-16]. Thus, it would be advantageous to have a surface coating platform that can be readily modified to tune the blood half-life and/or other characteristics of SPIONs for desired applications. It is also important that the biodistribution and clearance is via well-defined pathways; for example, for patients with Chronic Kidney disease it is important that in vivo tracers administered for MPI are clear not by the Kidney but by the liver and spleen.